GENETIC FINE MAPPING IN SLE PAIR FAMILIES

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The familial clustering of systemic lupus erythematosus (SLE) and the high rate of concordance in monozygotic twins suggests a strong genetic component for susceptibility to SLE. As one approach to the identification of lupus genes, our laboratory is currently performing a genome-wide marker screen in an effort to localized the chromosomal regions that harbor lupus genes. Over 180 families with at least two affected SLE relatives (mostly sib pair families) are enrolled in this study. In preliminary studies, three distinct regions of human Chromosome 1 show evidence of possible linkage in an initial cohort of 105 SLE sib pair families. As the genome screen proceeds it is likely that other candidate intervals will emerge on other chromosomes. The primary goal of the SCOR project is to accelerate the gene search in the MN SLE family collection. This will be accomplished by sharing ongoing genotyping data with our colleagues at OMRF (project #2) to compare results in the two SLE family collections. Preliminary mapping results at MN will also be shared with our colleagues at UAB (project #3) to assist in their screening of Chromosome 1q candidate genes. The MN family collection will then be genotyped with markers from the OMRF study, so that linkage results can be directly compared. Interesting chromosomal regions ill then be prioritized for high density marker screens and fine mapping. Trio families (one SLE patient with both parents) collected as a component of this SCOR application will be used in disequilibrium mapping in the targeted areas. A variety of strategies will then be employed to identify the SLE gene(s) in these regions. The ultimate isolation and cloning of SLE genes will provide the first opportunity to understand at the genetic level the defects that lead to the clinical immune dysregulation characteristic of patients with lupus. These insights should suggest new avenues of treatments for this patients, including the potential for somatic gene therapy. Interestingly, lupus- prone families also have an increased incidence of other autoimmune diseases including rheumatoid arthritis, thyroid disease, and diabetes. Thus, the identification of genes that cause human SLE is likely to improve our understanding of the genetics and pathophysiology of organ- specific autoimmunity.